Recruiting children to participate in clinical drug trials is an activity closely scrutinized by regulators, bioethicists, ethics committees, institutional review boards, and the popular press. The FDA acknowledges the vulnerability of pediatric subjects and has implemented heightened regulatory safeguards. Pediatric clinical trials represent a powerful, emotional platform because of the potential for conflict of interest among a number of parties, including pharmaceutical company sponsors, study investigators, and parents.	

A number of consumer media articles have detailed these conflicts and the implicit or explicit "exploitation" of children. As noted in a prominent northeastern newspaper, "an examination of research in children since 1994 shows that the potent combination of vulnerable children, ambitious researchers, potential profits, and weak oversight can hold great peril for these children."1 This media attention comes against a backdrop of children as "therapeutic orphans" who have historically been excluded from the drug development process. Indeed, many drugs prescribed for children have never been tested under controlled clinical trial conditions in a pediatric population.	

Recent and ongoing legislation initiatives, incuding the BPCA, the Pediatric Rule, and the proposed Pediatric Research Act of 2003, have and will contiue to transform pediatric clinical trials into an integral part of the drug development process. The demand for pediatric subjects and the recruitment challenge to fill clinical trials quotas have been described as a "frenzy"2 and exacerbate concerns regarding adequate protection of pediatric subjects. Although there is an ongoing debate over the benefits and pitfalls associated with pediatric clinical trials, there is relatively little comment from parents and their children on their motivations and experiences associated with participating in clinical trials. 	

The few surveys that have been conducted focused on adult subjects' experiences in clinical trials. In 1982, Cassileth et al. reported the results of a survey of 295 subjects representing cancer and cardiology patients and members of the general public.3 Most (71%) responded that patients should serve as research subjects primarily for altruistic motives. The authors noted that respondents "view clinical trials as important, ethical, and a means of attaining superior clinical care."	

Findings of a 1999 CenterWatch survey of 210 randomly selected volunteers who had participated in a clinical trial within the previous year note that "the vast majority of patients have positive experiences participating in clinical trials."4 Nine out of 10 respondents described the quality of care and attention they  received during the study as "excellent" or "good," and the vast majority (98%) responded that they would consider participating in another clinical trial.	

The "2001 Will and Why Survey," conducted by Harris Interactive and BBK Healthcare, surveyed 5000 respondents  representing a demographically balanced sample of the general public.5 Again, the survey findings highlighted the positive experiences of trial subjects. The authors also noted that "the survey supports the belief that clinical research studies are perceived by the public as treatment options."	

Objectives. A pediatric survey aimed to determine the specific factors that parents and their children consider before enrolling in a pediatric clinical trial, including				

their experience and satisfaction level associated with participating in the study.

their interest in enrolling in future trials, based on their trial experience.

Methods. Respondents represented participants enrolled in 21 pharmaceutical industry–sponsored Phase 1–4 studies conducted at Pediatric Clinical Trials International (at Columbus Children's Hospital) during May–December 2001. A total of 132 respondents (74 parents and 58 subjects age 9 or older) completed a three-page, self-administered questionnaire. Key respondent demographics are shown in Table 1.	

The questionnaire asked how they became aware of the trial and for their specific reasons for enrolling in the study, their satisfaction with treatment, and their intent to enroll in future studies. Respondents had completed at least 50% of the treatment associated with their specific study. The wording of the questionnaire was modified to be child-friendly, and parents were asked to check to see whether their child understood and completed all questions. 	

Subjects were enrolled in studies representing a wide range of therapeutic areas as outlined in the Therapeutic Areas box.  	

Parent and subject awareness. Parents and their children become aware of pediatric clinical trials through a wide range of sources (Table 2). Parents became aware of studies primarily through advertising (33%) and their physician (20%). Children cited their parents or other family member (47%) as the primary source. Almost half (42%) of respondents reported that they called for details related to a study within 24 hours of becoming aware, and over two-thirds (70%) inquired within 48 hours. Nearly half (46%) reported hearing about the study more than once before calling for details. Of those who became aware of the study from a source other than their physician (n=72), more than half (56%) did not get their physician's opinion of the study.						

Parent and subject motivation. Reasons for deciding to participate in a clinical trial are presented in Table 3. The primary reason cited was the belief that the clinical trial therapy would improve the child's condition, since current and/or alternative treatments were either ineffective or unavailable (88% parents, 52% subjects). Nearly half of parents (47%) and a somewhat smaller number of subjects (38%) reported altruism as a significant motive for enrolling in a trial. Half of the subjects (51%) and a quarter of the parents (27%) cited financial compensation as a factor in their decision to participate. A majority of parents (53%) mentioned that their child's condition had been diagnosed for at least one year, and 22% reported a diagnosis of five years or longer. Parents were queried why their child was treated in a study rather than receiving care from their physician, hospital, or clinic (Table 4). Once again, the desire to identify more effective treatments and altruistic motives were cited as driving factors.	

Parent and subject experience. Virtually all parents and children stated that the level of medical care at least met expectations, with a majority of parents (72%) and subjects (69%) commenting that it was better than expected (Table 5). As a result of this high level of satisfaction, all the parents and about three-quarters of the pediatric subjects would consider enrollment in another clinical study (Table 6).

Respondents view pharmaceutical industry–sponsored clinical trials as an important treatment option, and both parents and their children reported a combination of altruistic and nonaltruistic motives as driving factors for participation. Despite unbalanced media reports of pediatric trials, both parents and children cited high satisfaction with their experience and interest in participating in a future trial. Participation and satisfaction were reported across a wide demographic range.				

Compensation of pediatric trial participants is a sensitive area. A significant number of parents and patients cited being paid to participate as a motivational factor. It is noteworthy that 61% of study participants were adolescents (13–21 years of age), who as a group are more responsive to monetary incentives-and many were enrolled in Phase 1 studies, in which there may or may not be any clinical benefit. 	

The reputation and perceived ethics of the participating institution and the physician relationship play important roles in the decision to enroll a child in a study. A high percentage of parents became aware of the clinical trial through their physician, or consulted with their physician as to the study's merits. One exception is among parents with children afflicted with behavioral health disorders. In general, this latter group made the decision to participate in a behavioral health clinical trial with little or no consultation with their physician-primarily due to their dissatisfaction with their child's current or previous therapies. 	

Selective use of media advertising is an effective tool for identifying prospective pediatric trial subjects. Media advertising is most effective when multiple impressions are made in a short period of time. The effectiveness of advertising tactics can be rapidly assessed, because the decision to take action and call for details related to a study is made quickly.	

As a final comment, it is important that the consumer media present a balanced picture of pediatric clinical trials. Mass media can be a powerful educational vehicle. Presenting an unbiased assessment of both the pros and cons associated with pediatric clinical trials helps parents make informed healthcare decisions on behalf of their children.	

1.	A. Dembner, "Dangerous Dosage to Make Pediatric Medicine Safer: Thousands of Children Are Being Used to Test Drugs Originally Designed for Adults," Boston Globe A1 (Feb. 18, 2001).				

2.	R. Zimmerman, "Desperately Seeking Kids for Clinical Trials," Wall Street Journal A1 (May 29, 2002).	

3.	B.R. Cassileth, E.J. Lusk, D.S. Miller and S. Hurwitz, "Attitudes Toward Clinical Trials Among Patients and the Public," Journal of the American Medical Association, 248 (8) 968–970 (1982).	

4.	CenterWatch, "The 1999 CenterWatch Survey of Study Volunteer Experiences," CenterWatch, 6 (6) 1 (June 1999).	

5.	"The Will and Why Survey," BBK Healthcare, Inc./Harris Interactive, June 2001.	

John Niles, MS, MBA, is CEO of Pediatric Clinical Trials International at Columbus Children's Hospital in Columbus, Ohio, (614) 722-2551, fax (614) 722-2662, e-mail: 

Articles

Feature Article

Pediatric trials got a good report card from a survey that explored the motivators and experiences of young subjects and their parents.

Pediatric Subjects and Their Parents

The timetable for European Union plans to bring clinical trials more fully into the world of information technology has emerged. At the end of July, an outline was agreed upon by an obscure but influential group of experts on what should happen next for clinical trials in the esoteric world of telematics and pharmaceuticals.   

The priorities the group sets out for clinical trials in medicines for human use are to provide information technology (IT) support for the implementation of the EU rules on clinical trials (Directive 2001/20/EC), to develop a database of reports of Suspected Unexpected Serious Adverse Reactions occurring during clinical trials (SUSARs), and to develop a database of information on clinical trials.   

The first deadline is the end of this year. A first iteration of the SUSARs database is now scheduled for December 2003. This will be followed—according to the timetable set by the telematics experts—by production implementation of the SUSARs database by April 2004. Later in 2004, a first version of the database of information on clinical trials (known as EudraCT, and foreseen in the clinical trials directive) is scheduled for development, and by 2005 it should be extended, upgraded, and modified as necessary. The European Agency for the Evaluation of Medicinal Products is envisaged as the responsible body for carrying out the program, and the money for it is foreseen to come from the EMEA budget.   

The Telematic Steering Committee—as the expert group is known—specified implementation priorities, objectives, timetables, and budgets for half-a-dozen key pharmaceutical regulatory activities: notably the Euro PHARM Database, the projected European pharmaceutical database of harmonized information for all authorized medicines, in all EU official languages, with different levels of entry and inquiry for general public, physicians, and regulators. But it also covers EudraNet, EudraVigilance (a system to optimize monitoring of the safety of medicines on the market throughout the EU, permitting safe and fast exchange of information, from industry, between regulators), E-Submissions and EudraTrack, as well as clinical trials. It urges the creation of specific mechanisms and audit procedures for monitoring the relative progress of each project, and specific financial road maps for budgetary control. 

Behind these projects is a strategy the EU has been working on for more than a year “to provide guidance for the development and operation of the structure of the pharmaceutical IT systems.” The main objectives of European pharmaceutical policy and legislation remain the same—a high level of protection of public health, a single market for pharmaceuticals, competitive capacity for the European pharmaceutical industry, and preparations for EU enlargement in 2004. But putting policies and legislation into effect is increasingly dependent on effective IT solutions. 

The strategy has been agreed between member states, the European Agency for the Evaluation of Medicinal Products and the European Commission. The Telematic Steering Committee is in charge of its monitoring and development. Among the broad objectives are to: 

	bring more efficiency into the operation of the EU regulatory procedures on medicines marketing and surveillance. 

	allow safe exchange of information within the system.

	involve pharmaceutical companies so as to promote e-submission and e-reporting. 

It claims to ground its initiatives “in the real and, if possible, validated needs of users.”  

Before the summer break, the European Commission released updated guidance for good manufacturing practice (GMP) for investigational medicinal products. This is another of the detailed measures implementing the EU’s clinical trials directive, but it also takes account of the requirements of the experience of industry and regulators. (The updated guidance takes the form of an updated Annex 13 to the EC Guide to Good Manufacturing Practice, providing supplementary guidance on the application of the principles and guidelines of GMP to investigational medicinal products.) 

The underlying principle is that investigational medicinal products should be produced in accordance with the principles and the detailed guidelines of Good Manufacturing Practice for Medicinal Products (The Rules Governing Medicinal Products in The European Community, Volume IV). But, it says, in clinical trials “there may be added risk to participating subjects compared to patients treated with marketed products,” and applying GMP to the manufacture of investigational medicinal products is intended to ensure that trial subjects are not placed at risk and that the results of clinical trials are unaffected by inadequate safety, quality, or efficacy arising from unsatisfactory manufacture. Equally, it is intended to ensure that there is consistency between batches of the same investigational medicinal product used in the same or different clinical trials, and that changes during the development of an investigational medicinal product are adequately documented and justified. 

The guideline recognizes that there are additional complexities in the production of investigational medicinal products in comparison to marketed products: 

	The variety of clinical trial designs, consequent packaging designs.

	The need for randomization and blinding.

	The increased risk of product cross-contamination and mix up. 

There may also be incomplete knowledge of the potency and toxicity of the product and a lack of full process validation. Marketed products may be used which have been repackaged or modified in some way. 

So what’s needed, the guideline insists, is personnel with a thorough understanding of, and training in, the application of GMP to investigational medicinal products. Cooperation is required with trial sponsors who undertake the ultimate responsibility for all aspects of the clinical trial, including the quality of investigational medicinal products. And the increased complexity in manufacturing operations requires a highly effective quality system. 

The vague EU plans for action to promote the development of pediatric medicines (see this column, ACT June 2003) are not evolving fast enough for some EU member states. Belgium has raised the matter at the EU Council of Ministers, and urged faster action.  

Belgium pointed out that as far back as December 2000, the EU Council of Ministers for Health asked for proposals to be made “as soon as possible” for agreement at European level on incentives, regulatory measures or other supporting measures in respect of clinical research, and development targeted at pediatric medicinal products. The aim then—and now—is to ensure that new medicines and products already on the market are adapted to the specific needs of children. At the same time, the ethical aspects of clinical trials involving children and the internationally acknowledged standards for the protection of minors with regard to medical scientific research “should also be taken into account.” 

It is now more than a year (February 2002, in fact) since work started on a draft regulation to promote medicines intended for children, Belgium remarked, but despite the preparations by the European Commission (the EU institution whose job it is to make formal legislative proposals), “the Council and the Parliament have received no formal proposal to date.” Belgium went on its statement to emphasize “the precariousness” of the present situation. The pharmaceutical industry, said Belgium, is waiting, “indefinitely postponing submission of registration dossiers for pediatric medicinal products in the expectation of the probable incentives in the new regulations to come.” 

So Belgium urged the Council and the Commission “to take stock of the issue with a view to satisfying the needs of the European pediatric population without delay.” The Council formally took note of the Belgian intervention—which is a polite way of saying none of the other member states disagreed violently, but there was no rush to join Belgium on the barricades, either. For its part, the Commission again told the Council what was already well-known, in a well-rehearsed formulation: that “after the consultation process launched in February 2002, it expects to be in a position to present a proposal on child-specific medicines possibly at the end of this year or during the first quarter of 2004.” Meanwhile, as ACT has already reported, an extended assessment of ways and means is planned by the Commission for later this year—but has still not started. 

View from Brussels

As information technology becomes more important to clinical trials, the EU is discussing how IT should be included in clinical trials legislation.

EU to Put the IT into Clinical Trials

As research subjects, children have special needs because of their vulnerabilities and developmental peculiarities. Doctors involved in research on children must respect the autonomy and the individuality of children, be aware of children’s apprehension about medical procedures, and acknowledge the fundamental biological differences between adults and children. In this article, we will review some of the ways in which pediatric trials differ from adult trials and discuss some of the practical and ethical issues that remain to be solved. 

Consider, for example, that in the year 2000, the European Union had about 75 million children and 45,000 pediatricians, but only 12 clinical pediatric pharmacologists. Pediatricians have been informed of the problem of unlicensed and off-license pharmaceutical use, but such use is commonplace. In the United States, the Food and Drug Administration (FDA) Modernization Act and its successor, the Best Pharmaceuticals for Children Act, provide companies a six-month patent extension in recognition of adequately conducted pediatric trials.

A European conference held in Brussels in January 2002, co-hosted by the European Forum for Good Clinical Practice (EFGCP) and the Confederation of European Specialists in Paediatrics (CESP), addressed the ethical, scientific, and regulatory issues in pediatric research. Both authors of this article participated.

The need for pediatric researchIn 1989, the United Nations General Assembly approved a Convention on the Rights of the Child.

 The following four principles articulated in this declaration are of fundamental importance in pharmaceutical studies:

	All human rights apply to children without exception. 

		All interventions must have the child’s best interest as a primary consideration of the highest priority. 

		Children have the right to the highest attainable level of health. 

		Children have the right to obtain information and the right to respect of their opinion. 

Optimal medical care is based on evidence-based intervention. There are, however, significant deficits in our current knowledge of the quality and efficacy of many therapeutic measures in children, 

 and much pediatric therapeutic data is derived from studies in adults. 

 In fact, children have been described as “therapeutic orphans” because of the deficit of appropriate studies in their age group. 

 As a result of this deficit, about 50% of medications used in children’s hospitals are not properly licensed for use in children. 

Many differences exist in physiology, pathology, pharmacokinetics, and pharmacodynamics between children and adults. 

 For example, in pharmacokinetics, there are differences in metabolic pathways, in organic functions, and in metabolic rates. In pharmacodynamics, differences exist in receptor functions, effector systems, and homeostatic mechanisms. Growth and development influence side effects, and the dose of medications is dependent on body weight or surface area. Finally, age influences severity of disease, pathological agents, and natural history. These differences imply that extrapolation of adult data on medicinal products for the child population is inappropriate. 

Furthermore, childhood has several ages and stages. Studies must be performed on specific age groups such as premature newborns, full-term newborns, infants and toddlers, older children, and adolescents.

The FDA, EMEA, and other authorities state that research in children should be supported and encouraged. The Committee for Proprietary Medicinal Products (CPMP) recommends the following categorization of products to be studied in pediatric clinical trials: 

	medicinal products for diseases affecting children exclusively, such as surfactant in neonates

	medicinal products intended to treat diseases that mainly affect children, or are of particular gravity in children, or have a different natural history in children

	medicinal products intended to treat diseases occurring in adults and children, for which there is currently no treatment

	medicinal products to treat a disease occurring in adults and children for which treatments exist, but where there is insufficient knowledge of efficacy or toxicity in children. 

When should pediatric trials begin?One ethical issue pediatric researchers face is the fact that clinical research involves some risk to the subjects. Research procedures range from techniques involving minimal risk, such as questioning, observation, and measurement carried out sensitively, to techniques involving higher risk, such as chemotherapy and surgery. Risk is greatest in the early phases of clinical research. At what point in a drug’s development should research in children begin? The International Conference on Harmonization of Technical requirements for registration of Pharmaceuticals for Human Use (ICH) makes several suggestions regarding the inclusion of children in the development program of medicinal products. 

 For medicinal products for diseases affecting children exclusively or predominantly, the entire development program can be conducted in the pediatric population beginning with phase 1 or 2 trials. For products for serious diseases affecting both adults and children for which a sufficient treatment does not currently exist, the development program should be conducted early in the pediatric population after safety and tolerability data have been obtained in adults (phase 2 or 3). For other products for serious diseases, the product usually should not be tested in the pediatric population until phase 2 or 3, after substantial experience in adults.

In all cases, efficacy, pharmacokinetic, and safety studies must be performed first in animals, as is required for adult studies. Placebo-controlled trials are inappropriate in pediatrics when risk would be increased by withholding a proven, effective treatment. 

Good clinical practice issuesNo child should participate in a study unless a benefit to children in general will result. The ICH notes that the benefit to the individual and the benefit to the group must be balanced, as follows:The ethical imperative to obtain knowledge of the effects of medicinal products in paediatric patients has to be balanced against the ethical imperative to protect the individual child in clinical studies and respect his/her integrity and personal dignity.Good clinical practice (GCP) helps maintain that balance by ensuring that subjects are properly protected in research studies; studies are based on good science, well designed and properly analyzed; and study procedures are properly undertaken and documented. If GCP is not followed, children who take part may be at risk, the data may be unreliable or unusable, and the study should be rejected by the ethics committee.

Good clinical practice follows the general principles of medical ethics: 

	respect for life, human dignity, and personal autonomy

From these ethical principles, general guidelines for good clinical practice in pediatric research can be derived. 

 Trials should focus on the knowledge, cure, relief, or prevention of diseases of children. Biomedical studies must be devoted to reducing suffering and improving the prognosis of diseases. Expected benefit must exceed recognizable risks. Serious predictable risks should be avoided. Only well-designed studies are ethically appropriate. Study protocols must be evaluated by ethics committees (institutional review boards) and reviewed by experts in pediatric issues. Informed consent or assent must be obtained from the child participant and informed consent from the legal representative, according to national law.

Detailed operational guidelines for clinical investigations of medicinal products in the pediatric childhood population are provided by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). 

It is imperative that pediatric studies be performed by medical and scientific personnel who are familiar with good GCP guidelines and are capable of a trusting relationship and communication with the child and parents. Studies should be performed in institutions that provide a child-friendly atmosphere with a pediatric infrastructure and personnel.

Ethics committees are an effective instrument to protect subjects from inadequate research. An ethics committee that is going to review pediatric research should have members experienced in working with children. A European study (1998) showed that local committees usually review pediatric studies, because there are only a few national committees examining research projects in children. CESP recommended in 1998 that all national pediatric specialties establish Ethics Committees and that the interests of children should be represented on these committees. 

Informed consent and assentOnce the ethics committee has approved a properly designed study, the problem of obtaining consent or assent from children and their parents arises. The latest version of the Declaration of Helsinki

 suggests that for a legally incompetent minor, the investigator must obtain informed consent from the child’s legally authorized representative in accordance with applicable law. Even a legally incompetent minor may be able to give assent to decisions about participation in research, and in such cases the investigator must obtain that assent in addition to the consent of a legally authorized representative.

The Ethics Working Group of CESP gives several recommendations on this subject. The informed consent and assent process for including children in biomedical research should include all the information and consideration generally accepted for seeking informed consent of competent adults. Investigators should not place any coercion or undue influence to participate on the children’s parents. Dignity, privacy, and confidentiality of the child and family must be ensured. Information provided to children should conform to their intellectual capacity to understand the reason for the research and the risks therein. The family should be given sufficient time and information to consider the pros and cons of their involvement. Separate age-appropriate information sheets and consent or assent forms should be developed for the parents or legal representatives and for the child. A child should be able to withdraw willingly from any research project without detriment. In general the consent of both parents should be sought prior to enrolling a child in a biomedical research project. However, in some countries the consent of one parent is deemed adequate.

Recruitment issuesEven if sponsors are eager to perform studies in children, and the trial protocol has been carefully designed to meet their needs, recruiting pediatric subjects may be difficult. Parents seem to be becoming increasingly reluctant to enroll their children in basic research with no perceivable immediate benefit. As with adult trials, it is easiest to recruit children into trials when the standard therapies are unsatisfactory and the illness is inevitably lethal, as in cystic fibrosis and leukemia. Many parents have difficulty understanding placebo-controlled trials, and when they do understand them, they often have reservations about enrolling their children in them. An increasing number of antibiotic clinical trials are conducted in developing countries because it is easy to recruit subjects there, a trend that has raised ethical concerns.

In our experience, parents commonly raise several objections to enrolling their children in trials. Fear of harming or hurting children, especially by extensive blood sampling, objections to using children as “guinea pigs,” misconceptions regarding the need for placebos, and the increasing complexity of information sheets all contribute to parents’ reluctance.

Children themselves may be less reluctant than their parents. In 2001, an unpublished study of 30 families performed in Children’s Hospital in Dublin showed that 23% of parents would allow their child to participate in a clinical trial of an antibiotic with a license for adults, whereas 45% of children would be willing to take part.

However, the issue of childhood assent is contentious. An intellectual age of seven years has arbitrarily been recommended for including children in the assent process. One of the authors concluded from a small study that children under 10 years old did not fully understand the complexities of clinical trials and what they were being asked to assent to. Although parents are expected to sign the consent documents, should the verbal assent of children suffice, or should they be asked to sign something saying that they had been informed of the risks and assented, or did not dissent?

Other ethical issuesThe age at which children should become involved in the assent or consent process is just one question that must be studied and defined more clearly. Other ethical questions also constantly arise when sponsors consider pediatric trials. For example, can healthy children participate in taste tests of pediatric liquid formulations? How does one define “minimum risk” in terms of venipuncture and sample collection? Should currently well children with cystic fibrosis participate in pharmacokinetic studies of inhaled aerosolized antibiotics? How should investigators handle the need for contraceptives for adolescents involved in therapeutic trials where teratogenesis may be of concern, such as trials of new antiepileptics? What are the standards for off-license, off-label drug use in very low birth weight infants (under 1 kg)? Do we need placebo-controlled trials when there is no existing comparator, as in the case of antiviral agents?

The case of aerosolized inhaled insulin demonstrates how many ethical gray areas there still are in pediatric trials. An adult study of this therapy has demonstrated effect, but has not established long-term efficacy or safety. A person on 40 units insulin daily by injection would require 400 units insulin by inhalation. Insulin-dependent diabetes mellitus is primarily a disease of children. The desire of most children with diabetes is to be rid of insulin injections. Should children with diabetes be allowed to participate in trials of inhaled insulin, or must they await adult studies? The following are just some of the ethical issues that would arise in such a trial:

	What are the pharmacokinetics and pharmacodynamics of such a dose? Insulin distribution and metabolism would have to be studied. 

	Assuming only about 10% of an inhaled dose is absorbed, would radio-isotope labeled studies of insulin deposition be required? 

	Are there potential deleterious effects of such a large dose, such as antibody formation? 

	Children with diabetes of five to ten years’ duration would be very willing to participate. They would likely have a good appreciation of the issues involved. They would probably be willing to risk potential side effects in exchange for perceived benefit (absence of injections!). Would it be appropriate to include children aged 12–16 years in such trials? 

Although encouraging efforts have been made to address these ethical issues in Europe and in the United States, 

 much remains to be discussed, as this one example shows. It will require the combined efforts of pediatricians, pharmacologists, researchers, manufacturers, and medical societies to move pediatric trials forward with the necessary speed and care.

References	1.	General Assembly of the United Nations, Convention on the Rights of the Child, 20 November 1989, 

	2.	R.L. Smyth and A.M. Weindling, “Research in Children: Ethical and Scientific Aspects,” Paediatrics 354: 21–24 (1999). 

	3.	National Institutes of Health, NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects, 

grants.nih.gov/grants guide/notice-files/not98-014.html

	4.	T.L. Chambers and R. Kurz, “Ethical Overview of Paediatric Research and Practice in Europe from the Ethical Working Group of the Conference of European Specialists in Paediatrics (CESP),” European Paediatrics 158: 537–540 (1999). 

	5.	C. Cote et al., “Is the Therapeutic Orphan About to be Adopted?” Paediatrics 98: 118–123 (1996). 

	6.	S. Conroy et al., “Survey of Unlicensed and Off-label Drug Use in Paediatric Wards in European Countries,” British Medical Journal 320: 79–82 (2000). 

	7.	Committee for Proprietary Medicinal Products (CPMP), “Note for Guidance on Clinical Investigations of Medicinal Products in Children,” CPMP/EWP 462 (1995). 

	8.	Directive 2001/20/EC of the European Parliament and the Council on the Approximation of the Law, Regulations and Administrative Provisions of the Member States Relating to the Implementation of Good Clinical Practice in the Conduct of Clinical Trials on Medicinal Products for Human Use, 4 April, 2001, 

Services/Doc/clinical-EU-directive-04-April-01.pdf. 

	9.	International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), Note for Guidance on Clinical Investigation of Medicinal Products in the Paediatric Population. ICH, Topic 11, 

10.	T. Chambers, “Seven Questions about Paediatric Research,” Journal of the Royal Society of Medicine 93: 320–321 (2000). 

11.	P.J.J. Sauer, “Research in Children,” Report on behalf of the Ethics Working Group of CESP, European Journal of Pediatrics 161: 1–5 (2002). 

12. Royal College of Paediatrics and Child Health, Ethics Advisory Committee, “Guidelines for the Ethical Conduct of Medical Research Involving Children,” Archives of Disease in Childhood 82: 177–182 (2000). 

13. World Medical Association Recommendations Guiding Physicians in Biochemical Research Involving Human Subjects. Adopted by the 18th World Medical Assembly, Helsinki, Finland, June 1964, and amended by the 29th World Medical Assembly, 1975; 35th World Medical Assembly, 1983; 41st World Medical Assembly, 1989; the 48th General Assembly, 1996; and the 52nd World Medical Assembly, Edinburgh, Scotland, October 2000 (The World Medical Association, Inc., PO Box 63, 01212 Ferney-Voltaire Cedex, France; 

14.	World Health Organization, Operational Guidelines for Ethics Committees that Review Biomedical Research, 

www.who.int/tdr/publications/publications/ethics.htm

15.	R. Kurz, “The Role of European Ethics Committees in Paediatrics,” Good Clinical Practice Journal 7: 22–25 (2000). 

16.	J. Wechsler. “Science, Pediatric Studies, and Surrogates,” Applied Clinical Trials, June 1999, 28–33. 

17.	J. Wechsler, “Ethics, Kids, and Sex,” Applied Clinical Trials, August 2001, 15–17. 

Both the pharmaceutical industry and regulatory authorities worldwide have recognized the need for more clinical studies in children. A recent European conference addressed the issues.

Practical and Ethical Issues in Pediatric Clinical Trials

Clinical trials conducted in multinational and multicultural environments are increasing and include more nontraditional  sites in Asia, Latin America, and Eastern and Central Europe. There appear to be clear economic advantages to performing trials in emerging markets. This article addresses how differences in infrastructure, language, and culture within multinational clinical trials can quickly cost time and real dollars. Citing current examples from industry, the article offers tips for controlling clinical trial costs and discusses how to prepare for these differences and manage them as they occur. 

The cornerstones of clinical trial research include infrastructure (facilities, equipment, and ancillary personnel), a pool of subjects, and investigator experience. The sponsor faces the costs of subject and investigator recruitment, data analysis, record keeping, adverse events, informed consent, and addressing protocol related audit findings. 

Since 1990, the scope of global research has grown from 28 to 79 countries, and the number of investigators conducting FDA research worldwide has multiplied 16 fold

. The International Conference on Harmonization E5 allows the use of foreign data in drug approvals. Nontraditional sites attract sponsors with the promise of lower costs for subject recruitment and investigator compensation. Some aspects of clinical development may cost less in nontraditional markets, but other aspects can cost more. For example, sponsors may have to invest in building new infrastructure, training more personnel, and traveling more frequently to monitor study sites and to build relationships with local regulatory bodies. 

Language and cultural differences among subjects and investigators may also necessitate staffing changes to accommodate differences in culture. Project cycle time may be increased by repeated interaction to correct translation errors. Schedules may have to be adjusted to accommodate differences in medical practice. 

Clinical trial managers who apply project management techniques to foreign clinical trials will first identify the goals of the clinical trial plan, and then examine the effects on cash flow elements. In Central and Eastern Europe, Asia, and Latin America, subject recruitment is likely to be faster than in traditional sites in the United States, Western Europe, Canada, Australia, and New Zealand. Many of these countries also offer a vast pool of treatment-naive subjects and equivalent or higher prevalence of diseases for which treatments are being developed.  

Despite these advantages, infrastructure needs at nontraditional sites may require sponsors to build clinics and supply computers and sample refrigeration systems. Telecommunications may be less reliable, requiring more international travel for trial managers and team members. Finally, seasonal differences, holidays, and national vacation schedules can significantly affect clinical development timelines. 

Managers should use a checklist (see sidebar) to compare the infrastructure costs of conducting a clinical trial in different regions. They may also use this checklist to factor in the likely financial impact of language and cultural differences. 

Sponsors are relying increasingly on English as a global language. Local physicians, however, work with patients in their native languages. The cost implications of this dichotomy include the cost of translating protocols, informed consents, questionnaires, source data, adverse event reports, and even training content.  

Potential costs associated with translation errors are even more significant. Repeated feedback to correct errors in translating administrative and research documents leads to increased cycle times.

 And if key terminology is left open to individual interpretation, a whole study may be compromised.  

Some sponsors may say there is no need to worry about language barriers because they require English fluency in their clinical development team. However, it may be useful to consider the caveat,  If there is one message, and 100 people to communicate with, one will have 100 messages, unless one is careful.  Most people using English professionally are not native speakers. About 1.2 billion people may speak English as a second or foreign language, while only 380 million can be counted as native speakers, a ratio of 3:1.

 What are the vocabulary and grammar qualifications that make one an English speaker? Do high marks on a written test ensure equal competence when English is used in face-to-face meetings or teleconferences? Sponsors should expect language related misunderstandings during the planning and conduct of a multinational clinical trial and prepare for them.  

How might mistakes show up in the process of a clinical trial, and how serious are they? Consider the common misunderstanding of  dose  and  dosage,  or  serious  and  severe,  even among native English speakers. It is more likely that these may be misunderstood and misapplied with nonnative speakers, with potentially significant impact. Unaddressed misunderstanding could compromise the integrity of the whole study and result in a multi million dollar error. Sponsors can avert misinterpretation by making all definitions explicit, through the use of a standard glossary, and through simultaneous translation during investigator training.  

Culture is a largely unspoken, shared agreement on deep values within a community. Culture is manifested as social patterns of speech and behavior. Many emerging clinical trial sites differ from traditional markets in that deep values within the culture favor the community over the individual. Social status is revered, as are behaviors geared toward building long termrelationships.    

Cultural values and behaviors present benefits and challenges for those sponsoring multinational clinical trials, in terms of internal management and external relationships with subjects, investigators, and regulatory bodies. Internally, sponsors may have to opt for more senior personnel to be involved. Externally, cultural differences influencing medical practice and patient behavior are likely to show up in the course of a clinical trial in key areas such as subject enrollment and compliance, scheduling subject visits, investigator compensation and training, informed consent, adverse event reporting, source data, auditing, and internal communications.   

These examples show how language and cultural differences may require additional attention and resources during a multinational clinical trial.  

Subject enrollment and retention is often faster and easier in nontraditional markets. Sponsors are drawn to these markets by the abundance of treatment-naÃ¯ve subjects within large urban centers with a hospital  infrastructure.  

One study estimates that in the United States, 66% of subjects enroll independently of their doctors. In Latin America 80% of subjects are offered enrollment by their doctors.

 This difference is important when preparing recruitment plans and materials. 

Religion may also affect enrollment, for example, in a trial requiring a complete sexual history from women in a predominantly Catholic country. If the basic premise of a trial is at odds with a sites culturally prescribed ethics (whether derived from religious or secular principles), a sponsor may consider selecting a different site, or modifying the protocol. Another option here may also be to use an experienced local partner for protocol preparation and subject enrollment.  

Subjects in some countries are very compliant and eager to attend all study visits. They tend to listen to their doctors and follow orders unequivocally. In Russia and Japan, for example, a culture of compliance  dictates that patients follow doctors  orders explicitly. This tradition presents a benefit to sponsors enrollment is quick and retention is high.  

One corollary to this  culture of compliance  is that subjects (in Russia and Japan, for example) may not readily report adverse events. They may not complain, because they don t want to jeopardize their status as a participant or lose access to medical treatment or they may be too sick. Investigators may need training to actively solicit adverse events from subjects.

The culture of compliance  may also create difficulties in documenting informed consent. Japanese and Russian subjects and their families traditionally prefer the attitude of I put myself in your hands, doctor.  A full informative discussion of risks requires investigators in those countries to break the pattern of treating patients without sharing with them the sometimes frightening details of their illness.  

In countries with low literacy, permission may not be documented on a form.

 Regulators may have difficulty confirming that subjects received proper information about risks and benefits, and that their participation was not coerced. 

Sponsors need know about differences in medical practice. In Latin America, a typical physician schedule includes hospital rounds in the morning, and afternoon work in private clinics. Hospital staff, required to help a principal investigator during subject visits, may only work in the morning.

Source data may not be saved. If they are, they may be illegible, handwritten notes in the local language, making translation difficult. The sponsor can opt to remain at the site or to find another where source data is traditionally kept. If there are other benefits for staying at a particular site, sponsors may need to budget additional resources to train site personnel on standard operating procedures (SOPs) for source data and quality standards, to supply computer equipment and computer support, to provide templates to ease recording, and to ensure that site staff members are computer literate.

Investigators may be participating in a clinical trial because it increases their status in the community, a powerful incentive in relationship-based cultures like India and Latin America. Sponsors may solidify investigator dedication by including key regional investigators in scientific publications and presentations at conferences and symposia.  

Investigators and subjects often use local languages during their interactions. Data and hospital records may be recorded in the local language, requiring translation.  

Local expressions for symptoms and ailments may be translated literally, misleading data analysts. For example, in some developing countries, subjects may describe a respiratory infection with a phrase that literally translates as  stomach moves in waves,  suggesting a problem with the stomach, rather than with breathing.

 Literal translations may require sponsors to send repeated queries for clarification. Worse, sponsors may not recognize the report as an error, compromising the study. 

Learning methods and investigator training

Cultural differences influence investigator training, in terms of choosing who participates in the training and which learning methods and support materials will be effective with that audience. Resident physicians in Latin America may fill out the case report forms themselves, a role that defines them as important audience members. Sponsors must also consider hierarchy when inviting participants. Superiors may feel overlooked if they are not invited when subordinates are, even if it is the subordinates who actually need the training.  

Learning methods also vary. Americans and Canadians often prefer to jump to the end of a lesson. Pacific Rim learners may prefer a sequence featuring theory followed by a learning experience. Europeans may favor a high volume of detail and structure.  

To address variations in language fluency, sponsors should also address the content of training materials. If published in English only, sponsors may benefit from providing them to participants in advance, so that they have a chance to prepare comments and questions for the meeting. Graphics and diagrams may also be used to bridge language barriers, although care should be taken to consider the cultural appropriateness of images. Sponsors may consider publishing some key training materials in local languages. Finally, if simultaneous translation is used during the training, sponsors should ensure that the translator is also technically fluent in the appropriate medical field, and allot twice the amount of time they normally would for that portion of the training. 

Input errors and varied terminology may lead to duplications in reporting, and other inconsistencies that are difficult for auditors to interpret.

 One alternative is for sponsors to invest in a computer-based audit management system with key words for major findings and centralized templates for reporting findings and documenting action plans.  

Staffing the clinical trial and quality assurance teams

Differences in cultural values, specifically around collaboration and hierarchy, play a role in the degree of cross-functional involvement in developing protocols and staffing quality assurance teams. In general, individual and department roles may be more specifically defined, and more senior people may be involved than in comparable organizations in the United States.   

In Japan, for example, protocols are approved at a high organizational level, and development may involve specialists from Clinical Development, Statistics, Regulatory Affairs, and Drug Supply. In contrast, Western companies enlist broad support, adding Quality Control, Drug Discovery, Project Planning, and Marketing to the protocol development team. 

In contrast to the United States, physicians are routinely among the staff of German Quality Assurance departments.

  Finally, cultural differences influence rigorous regulatory compliance, which affects the projects target standards. The Japanese, for example, may tend to set standards of quality assurance so high that partners fear they are unachievable.  

A sponsor may choose to globalize quality assurance by taking some concrete steps including a Partnership Approach within the clinical trial organization. International management teams share responsibilities for preparing audit plans, budgets, workload distribution, and strategy. Furthermore, auditors from corporate management partner with those from site quality assurance into joint audit teams to help smooth out language and cultural barriers at lower levels in the organization.  

Sincere respect for unique cultures and their differences is the first step in building best practices for conducting a multinational clinical trial. Applying a partnership approach to build supportive external relationships is likely to serve sponsors well, especially in relationship-based cultures. Sponsors should continually seek opportunities to develop relationships with local regulators, as well as with investigative sites in academia, public hospitals, and private institutions. Investigators, study coordinators, and clinical development team members should experience training about the cultural differences they are likely to encounter, and learn appropriate ways to handle those differences.   

Accurate translation is the key to handling language-related issues. Training materials and forms should be prepared in local languages, and a simplified version of English is recommended for international meetings and correspondence. Sponsors should also choose translators who are technically fluent in the terminology of the relevant medical field. 

Sponsors who prepare for differences between national infrastructures, languages, and cultures, and who allow for the unexpected, will succeed in controlling costs and cycle times and in building strong development teams around the world.   

1.		Office of the Inspector General Report, The Globalization of Clinical Trials (OIG, Washington, DC, September 2001). 

2.		Clinical Trial and Regulatory Best Practices in Japanese Affiliates of Multinational Firms (Pittiglio Rabin Todd and McGrath. 1503 Grant Rd., Ste. 200, Mountain View, CA, 94040).

3.		Barbara Wallraff,What Global Language, The Atlantic Monthly, November 2000, 5264.

It is increasingly important for clinical trial personnel to break through the obstacles that language and culture present when conducting trials away from their home countries.

Multinational Clinical Trials: Breaking Language and Cultural Barriers

Many of the new medications that come into the Japanese market originate in foreign countries, because the pharmaceutical industry in Japan is comparatively small. Despite this, foreign companies still have difficulty obtaining approval in Japan because of continued hesitancy about the exchange of foreign data. The most successful pharmaceutical products in Japan are still manufactured by Japanese companies

. For example, Japan stresses safety over efficacy, and daily doses are typically lower in Japan than in either the United States or the European Union

. It also appears that for a majority of drugs, dose differences are not due to pharmacokinetic differences, but rather differences in medical practice or culture. 

Western companies have great interest in using foreign data to satisfy Japanese requirements for drug approval. And with the adoption of the Guideline on Ethnic Factors in the Acceptability of Foreign Clinical Data (available online at www.ich.org/pdfICH/e5.pdf), the Japanese became open to the use of foreign clinical data in applications for drug registration. ICH made it possible for the global pharmaceutical industry, in cooperation with Japanese regulators, to register medicines in Japan using data gathered abroad

. The willingness of other regions to use Japanese data is likely to emerge more slowly, primarily because the level of record-keeping detail and the Western ability to monitor and audit trials at the site level are relatively new concepts in the Japanese clinical trials environment.

Developing new medications is a painstaking, lengthy, and expensive process. The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (generally referred to as ICH) focuses on technical requirements for medicines that contain new drugs. Most new drug products are developed in Western Europe, Japan, and the United States. Consequently, when ICH was established, the founding members agreed to concentrate on registration in those three regions. The founding members of ICH represent regulators and industry in the European Union, Japan, and the United States—the EU, EFPIA, MHLW, JPMA, FDA, and PhRMA. 

In 1998, the ICH Steering Committee recommended adoption of the Harmonised Tripartite Guideline on Ethnic Factors in the Acceptability of Foreign Clinical Data, E5. The focus of the E5 guideline is on the use of data created in one region for regulatory filing purposes in another region. 

Furthermore, that same year the FDA released a guidance with the International Conference on Harmonisation, “Guidance on Ethnic Factors in the Acceptability of Foreign Clinical Data,” recommending strategies that allow application of clinical data collected in one region to be used for the support of drug and biologic registrations in another region

. This document allows for the consideration and evaluation of such factors as the medication’s efficacy and safety at specified dosage and dose regimens. It was developed to facilitate the registration of study compounds among ICH regions. The guidance also suggests specific regulatory and development strategies to expedite the drug approval process, to allow adequate evaluation of the influence of ethnic and racial factors on drug intervention effects, and to minimize the duplication of clinical studies.

Clinical data generated in foreign regions can be either complete or incomplete, with the acceptability of the data depending on whether it can be accurately extrapolated to the new region. Extrapolation is the key concept behind accepting foreign clinical data and is highly contingent on the completeness of the package

.Complete packages should include data that adequately characterizes the pharmacodynamics, pharmacokinetics, and dose response in a relevant population and clinical trial data establishing dose response, efficacy, and safety. Successful extrapolation of data is more likely if the drug class has already been approved in the new region. If foreign data does not meet these stringent standards, the regulatory authority may require additional clinical trials. These clinical trials may focus on different subsets of the population (for example, including patients with renal or hepatic impairment), distinct comparator groups at clearly specified dosages or dose regimens, or drug–drug interactions. 

If foreign clinical data can be accepted by extrapolation, it is not necessary to conduct bridging studies, because the data can be inferred based upon existing data only. However, if extrapolation is unsuccessful, then in order to be complete, the final data package must also contain “bridging” studies. Bridging studies are defined by the ICH E5 guideline as supplemental studies performed in the new region to provide pharmacodynamic or clinical data on efficacy, safety, dosage, and dose regimen in the new region. Bridging studies will allow extrapolation of the foreign clinical data to the new region. Ethnic sensitivity to the study medication should guide the need and nature of the bridging study. Medications with the following characteristics are sensitive to ethnic factors and may be subjective to bridging studies: 

	Steep pharmacokinetic curve for both efficacy and safety in the recommended dose range

	High likelihood of use with other medications

Bridging studies considered by the regulatory agencies in Japan can be categorized into Phase 1 pharmacokinetic–pharmacodynamic (PK–PD) comparative studies and Phase 2/3 efficacy studies. As a practical note, while Western countries use the term bridging studies for both types of studies, Japan reserves the term “bridging” for only the Phase 2/3 efficacy studies.

The Phase 1 PK–PD studies comparing the two populations are almost always necessary and can be performed outside of Japan using a population representative of Japan. The need for Phase 2/3 efficacy studies is evaluated on a case-by-case basis and usually must be performed in Japan. Situations where additional efficacy trials are needed occur when medical practices in the new region are significantly different, the choice of dose in the new region is unclear, the new region has little or no experience with controlled trials, or when the class of medication is unfamiliar in the new region.

Data generated from bridging studies may yield several possible results: 

	Efficacy, safety, and drug response are similar in the two regions, and thus capable of bridging the foreign data. 

	Data are not substantially different between the regions, and therefore may be extrapolated with the appropriate dose adjustment. 

	The data may not be of sufficient sample size to confirm extrapolation of the data, and additional safety and efficacy data may be requested. 

	The data may not confirm safety and efficacy in the new region; therefore, additional clinical trials in the new region would be required to confirm the study medication’s safety and efficacy. 

The concept of extrapolation and bridging discussed in the guideline is difficult to understand because the performance of the bridging study is not clearly described. Therefore, discussion of bridging study designs between the regional regulatory authority and the sponsor is encouraged prior to completion of the clinical data package. Designing the bridging study is crucial to the success of the program. In order to be valid, the bridging study must have the same design as the study conducted in the foreign region. More often than not, however, it is difficult to conduct an identical study because medical practices and therapeutic strategies may vary. Other issues that arise include differences in definitions and diagnosis of the target disease between regions. This can be overcome by choosing the definition and diagnosis used in either the foreign region or globally. 

Another example includes the choice of appropriate endpoints, which can differ from region to region. Endpoints that are commonly accepted in one region may not be widely recognized as the best endpoint in another region. Therefore, it is most appropriate to choose endpoints that have been globally used and validated. In addition, common medical practices and customs in distinct regions may greatly influence the appropriateness of endpoints. Therefore depending on choice of endpoint, data gathered from randomized, controlled clinical trials in one region may not be applicable in a new region, especially across ethnic differences.

As discussed before, whereas the Phase 2/3 efficacy trials must always be performed in Japan, the Phase 1 PK–PD comparative trials may be performed outside of Japan. Sponsors may have a number of reasons for wishing to conduct such studies outside of Japan. For example, 	

A compound’s clinical development is taking place outside of Japan.

Restrictive regulations and cultural differences make regulatory approval in Japan elusive, but adopting new strategies may make that lucrative pharmaceutical market more accessible to non-Japanese companies.

Applied Clinical Trials-09-01-2003

Pediatric Subjects and Their Parents

EU to Put the IT into Clinical Trials

Practical and Ethical Issues in Pediatric Clinical Trials

Multinational Clinical Trials: Breaking Language and Cultural Barriers

Bridging Strategies May Help Put Western Drugs on the Japanese Market

Research and Access Issues Challenge Policymakers

2003 IT Solutions Addendum